Breast Surgery research

Aims

Led by Professor John Robertson, the Breast Surgery research group’s aims are to improve the outcome of individuals with cancer.

Research issues

The group carries out a multipronged attack focusing on:

Early identification (breast, lung, liver and colorectal), as early diagnosis saves lives

With the increasing age of the population, gaining a deeper understanding of breast cancer in the elderly is especially important in order to target therapies most effectively

Sensitivity and mechanisms of resistance to endocrine and growth factor therapies

Clinical trials of new drugs for breast cancer treatment to improve patient outcome

Investigating the nature of the immune response in cancer, as a means of identifying novel tumour targets and or new immunotherapies

What we are doing about...

1. Early identification of cancer

The most common forms of cancer worldwide are lung, breast, colon, stomach, prostate and liver. For the first three early detection and treatment has now been shown in randomised clinical trials (RCT-Level 1 evidence) to significantly reduce mortality. This has confirmed the importance of earlier detection as a goal for all solid cancer types.

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Despite the fact that the clinical value of the three screening methodologies (i.e. CT scans, mammography and colonoscopy) have been confirmed; they also have their inherent limitations in terms of patient acceptance (e.g. mammography), potential side-effects (e.g. radiation or colonic perforation), expert staff requirements and cost. The reduction in deaths from these cancers due to screening has been calculated to be between 16% and 24%. There is therefore significant room for earlier detection and improved tests, which would save even more lives.

In almost all individuals who develop cancer (of whatever type – e.g. breast, lung,) the process of carcinogenesis may take from many months to years (even 20+ years). As such the immune system has been shown to recognise different proteins at different times in the process and make autoantibodies to them. The sequence of autoantibodies to different protein in cancer cells, or the pattern of autoantibodies provides information, which is clinically important for early diagnosis and for patient stratification for therapy and prognosis.

Current projects

a) Following the success of the early CDT lung test, research is being further carried out in lung and other cancers eg hepatocellular, colorectal, breast etc.

b) Research if being carried out in conjunction with the Immunology Division at QMC into new assay formats for detection of cancer

c) Psychosocial aspect of early cancer detection tests is being investigated in collaboration with Professor Denise Kendrick and Associate Professor Kavita Vedara.

2. Primary breast cancer in the elderly

The academic department of Breast Surgery has had a long-standing research interest in breast cancer in the elderly. We performed and reported two of the first randomised clinical trials on primary endocrine therapy versus surgery +/- adjuvant endocrine therapy. We reported the first of these in the BMJ in 1988 and recently reported long term follow-up on both these studies.

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Expertise

Our research interests include breast cancer, surgery and non-operative therapies, endocrine and targeted therapies, lymphoedema and clinical trials. Mr K L Cheung is a member of the Surgical Task Force of the International Society of Geriatric Oncology.

Specific research interests

Biology and clinical outcome – to characterise the biology of primary breast cancer in older women, to investigate the effect of age and ethnicity on tumour biology and to correlate with clinical outcome. Methodology includes analysis of biological materials (ie tumour tissues) and clinical data.

Geriatric assessment and psychosocial aspects – to develop a comprehensive geriatric assessment tool specific to the context of primary breast cancer, to investigate quality of life and psychosocial aspects, as well as decision making process. Methodology includes tool development and qualitative research.

Bioinformatics technology and principles will be exploited at the later stage to develop assessment tools based on tumour biology and geriatric assessment.

3. Hormone sensitivity and mechanisms of resistance to endocrine and growth factor therapies

The group has had a long standing interest in endocrine and growth factor therapies.

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We have been researching and publishing on markers which would predict sensitivity and resistance to hormone therapies since the late 1970s. Over the years resistance has been identified as de-novo (ie resistant from the start of treatment) and acquired (initially sensitive but subsequently develop resistance) and our group has published extensive on both areas.

Our contribution in the later in terms of human breast cancer studies has been significant - this has been facilitated by many patients who have participated in studies where biopsies of their breast cancer have been taken on treatment and then examined for biological markers. This work has carried out particularly in collaboration with the Department of Academic Pathology at The University of Nottingham and with the Tenovus Institute in Cardiff.

Based on the results of these studies which have shown various growth factor pathways altered and the new drugs being developed to target these same pathways our current research focuses on both endocrine and growth factor pathways.

The group has ongoing work in prognostic and predictive factors in breast cancer. A spin-off company called FaHRAS has been established, which has developed a software programme for assessing a woman’s risk of developing breast cancer.

The group has also had a long standing interest in blood tumour markers in breast cancer. In addition to our work on early detection we have also published extensively over 30 years on the use of blood markers in advanced breast cancer - help diagnosis and monitor treatments, particularly endocrine and growth factor therapies.

Results

Research in this area has led to a number of clinically significant outcomes. Initially with endocrine therapies clinicians looked to see the tumour decreasing in volume (ie ‘responding’) and if it didn’t they regarded this as ‘non-responsive’ and changed treatment.

Our group showed that there were over half the ‘non-responsive’ tumours where the treatment stopped the cancer growing (ie ‘stable disease’) and that these patients did as well as those where the tumour resonded by decreasing in volume. This lead to approximately 40% of patients being continued on endocrine treatments (until the tumour actually started to increase in volume) and thereby the patients continued to benefit from the long term treatment with these endocrine agents.

Our work has also led to improved selection of patients for endocrine and growth factor therapies based on clinical and biological characteristics.

Current projects

Research is continuing into the following areas:

Effects of age and ethnicity on biology of breast cancer

Sensitivity and resistance to hormone and growth factor therpies

Lymphoedema in breast cancer

4. Clinical Trials

The Breast Surgery group has been involved in clinical trials of breast cancer over the last 30 years - including, surgery, endocrine and growth factor therapies, radiotherapy, immune-based therapies.

5. Nature of the immune response in cancer

Current project

Tumour-infiltrating lymphocytes (TILs) are involved in controlling tumour growth and metastasis in various cancers and whilst this is predominantly attributed to cytotoxic T-cells, recent findings suggest a potentially central role for TIL-B cells.

TIL-Bs have been reported to be associated with favourable prognosis and improved patient survival in invasive ductal carcinoma (IDC) by ourselves and others, but have not been fully investigated in early disease.

Our aims are to:

Examine the presence of TIL-B cells in breast (and other) cancers in terms of presence, frequency and distribution, and association with disease outcome

Determine whether the aggregation of TIL-Bs in and around cancer tissue is the result of antigen-driven B-cell expansion

Produce recombinant antibody (scFv) from these TIL-Bs

Identify if antibodies associated with tumours are: a) tumour-specific or merely tumour-associated; and b) determine if these antibodies recognise a range of tumour-associated antigens

Outcomes

Spin-out company - Oncimmune Ltd.

This research at the University of Nottingham and international collaborations is already having a significant and positive impact on the outcome for individuals with lung cancer and the technology is translatable to all solid tumour types. Oncimmune, a university spinout company, has already launched the world’s first autoantibody test for the early detection of cancer.

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We have successfully developed a non-invasive blood test platform for the early detection of solid cancers. This bench to bedside research has been pursued in here for 17yrs and has delivered a world first diagnostic test - initially for lung cancer1-6 Our test (EarlyCDT-Lung) has been in clinical use in the USA since 2009 (following FDA oversight and CLIA lab approval).

An audit of the results from over 1600 individuals in the commercial setting has confirmed that the test performs as predicted1. EarlyCDT-Lung is now in a major Randomised controlled Trail in the UK (10,000 individuals) to provide support for its introduction into a national screening programme. We are progressing similar tests for Breast Cancer7,8, Liver Cancer9 and Colorectal Cancer moving along the translational pathway to clinical utility.

Two large prospective clinical trials are underway which the Centre of Excellence for Autoimmunity in Cancer (CEAC) has either initiated (US study, National Jewish) or is a partner in (Scottish study – 10,000 individual RCT) will also be impactful by providing level 1 evidence to include the test as an integral part of the national lung cancer screening programme. It will re-focus the screening strategy for other tumour types towards the autoantibody technology.

The group’s research has led to a number of patents in this area.

In addition to researching on tests for other types of cancer (eg breast, colon, liver) we are also working with colleagues in the Department of Immunology to develop a second generation of the autoantibody test using a different technology platform which we predict will be more sensitive and specific.

Media coverage

The clinical impact of this research has also been reported by various media: